Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pyrimidine nucleoside phosphorylase (PyNPase) converts 5'-deoxy-5-fluorouridine to 5'-fluorouracil, which exerts an anticancer effect before being catabolized by dihydropyrimidine dehydrogenase (DPD). Recently, PyNPase has been shown to be identical to a potent angiogenic factor, platelet-derived endothelial cell growth factor. We analyzed the concentration of PyNPase and DPD in 33 patients with esophageal squamous cell carcinoma in fresh-frozen samples by enzyme-linked immunosorbent assay. In addition, we evaluated the clinical significance and prognostic value of PyNPase expression in esophageal carcinoma. The PyNPase concentration of tumor tissue was statistically higher than that of normal tissue of the esophagus (248 +/- 146 U/mg protein vs 73 +/- 63 U/mg protein, P = 0.0001), whereas DPD showed no difference (90 +/- 62 U/mg protein vs 88 +/- 62 U/mg protein, P = 0.825). The ratio of PyNPase to DPD of tumor tissue was statistically higher than that of normal tissue of the esophagus (3.3 vs 0.95, P = 0.0001). There were no significant differences between the group with high tumor to normal tissue ratios of PyNPase concentration and the low-ratio group in terms of the tumor length, depth, lymph node metastasis, lymph vessel invasion, vascular invasion, stage and survival. In conclusion, 5'-deoxy-5-fluorouridine may be effective on esophageal carcinoma and PyNPase concentration in esophageal carcinoma may not be a useful prognostic marker for patients with esophageal squamous cell carcinoma.
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PMID:High level concentration of pyrimidine nucleoside phosphorylase in esophageal squamous cell carcinoma but no correlation with clinicopathological parameters. 1464 Dec 94

Thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) are considered to be key enzymes affecting the prognosis for patients with gastric and colorectal cancers. We tried to prove the correlation of TP and DPD expressions in gastric and colorectal cancers. The present study was designed to quantify TP and DPD levels by an enzyme-linked immunosorbent assay (ELISA) in tumors and normal tissues obtained from 16 gastric and 20 colorectal cancer patients. TP and TP/DPD ratio in the tumor specimens were almost all higher than those in each normal tissue, especially for tumors in the progressive state. In the early stage of the colorectal cancer group, DPD in the normal tissues were higher than those in the tumor specimens. There were no significant differences between TP levels in the tumor specimens of the two groups, whereas in stages III and IV, those of the gastric cancer group tended to be higher than those of colorectal cancer group. In stages I and II, DPD levels in the tumor specimens tended to be higher in the gastric cancer group than in the colorectal cancer group. DPD T/N was higher in the gastric cancer group than in the colorectal cancer group. There were no significant differences between TP/DPD ratios in the tumor specimens of the two groups, whereas those in normal tissue were higher in the gastric cancer group than in the colorectal cancer group. We may be able to achieve the successful effects or reduction of side effects of anticancer chemotherapy for gastric and colorectal cancer using the results of this study.
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PMID:Comparative analysis of thymidine phosphorylase and dihydropyrimidine dehydrogenase expression in gastric and colorectal cancers. 1506 45

Thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) are considered to be key enzymes affecting the prognosis for patients with advanced gastrointestinal cancer. Preoperative examination of TP and DPD expression levels and assessment of these enzymes in inoperable cancer patients may contribute to successful treatment. We tried to prove the correlation of TP and DPD expression in preoperative specimens by endoscopy and in surgical specimens. The present study was designed to quantify TP and DPD levels by enzyme-linked immunosorbent assay (ELISA) in tumor tissue obtained from 30 gastrointestinal cancer patients by preoperative endoscopy and surgery, including 15 gastric and 15 colorectal cancers. Successful cases as those in which cancer cells were demonstrated histologically in preoperative specimens by endoscopy were 12 (success rate: 80%) in gastric cancer patients, and 15 (success rate: 100%) in colorectal cancer patients. In successful cases, there were almost significant correlations in all cases, gastric cancer, and colorectal cancer among the expression of TP, DPD, and TP/DPD ratio in each preoperative specimen by endoscopy and surgical specimen, respectively. On the other hand, in the gastric cancer group, 3 unsuccessful cases resulted in a significant departure from ideal equation compared with 12 successful cases. In actual clinical care, physicians should pay attention to and evaluate carefully the data from endoscopical biopsy specimens in which cancer cells may not be demonstrated histologically. Thus, endoscopic analysis of TP and DPD expression in preoperative or inoperable cancer patients may contribute to successful treatment.
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PMID:Preoperative endoscopic analysis of thymidine phosphorylase and dihydropyrimidine dehydrogenase in gastrointestinal cancer. 1513 61

The study of the influence of genotype on drug activity and efficacy (pharmacogenetics) and the genome-wide approach to drug discovery and interpretation of complex pharmacological responses (pharmacogenomics) are gaining momentum in current molecular medicine. The reasons of the variable activity and tolerability of cancer chemotherapy are being unraveled by the discovery of genotypic alterations affecting pharmacokinetics and pharmacodynamics of drugs. Indeed, genetic variability may alter drug catabolism (i.e. dihydropyrimidine dehydrogenase for 5-fluorouracil, thiopurine-S-methyl transferase for thiopurines, aldehyde dehydrogenase for cyclophosphamide) and anabolism (i.e. thymidine phosphorylase for capecitabine, deoxycitidine kinase for gemcitabine). Moreover, increased expression of transporter systems (i.e. the ATP binding cassette (ABC) superfamily) is associated with reduction of the cytoplasmic levels of drugs which may be unable to exert a cytotoxic effect. Additional systems could protect tumor cells from drug cytotoxicity, including the DNA repair machinery (nucleotide excision repair (NER) and DNA alkyltransferases) and antiapoptotic systems (i.e. bcl-2). Finally, alterations of drug targets may be associated with a decrease in the effectiveness of chemotherapy (i.e. mutations affecting tubulin and topoisomerase I for taxanes and irinotecan, respectively, and increased expression of thymidilate synthase for 5-fluorouracil). Therefore, genetic analysis has the potential to predict treatment efficacy and tolerability. However, major problems encountered in pharmacogenetic and pharmacogenomic studies are the need of extensive validation of available technology, the difficulties in obtaining a suitable amount of tissue from patients during the course of their disease and the extremely complex regulation of gene function. From this perspective, the evaluation of the cellular effect of drugs in relation to protein expression and function (pharmacoproteomics) may be able to overcome these obstacles, and allow the optimisation of cancer chemotherapy in association with a pharmacogenetic approach.
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PMID:Pharmacogenetics of neoplastic diseases: new trends. 1520 12

Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) have been identified as a predictor of response to 5-fluorouracil (5-FU). Danenberg et al. developed a technology to evaluate gene expressions in formalin-fixed paraffin-embedded (FFPE) specimens (DTP; Danenberg tumor profile). In this study, TS and DPD gene expressions were measured in 47 primary colorectal cancer tumors and 12 metastatic tumors using FFPE specimens. In primary tumors, expression of TS genes in cancerous tissues was statistically higher than in stromal tissues, while DPD gene expressions in stromal tissues were higher than those in cancerous tissues. The median TS mRNA level was 0.86 in hepatic metastasis and 1.95 in lymph node metastasis. The median DPD mRNA level was 0.86 in hepatic metastasis and 1.96 in lymph node metastasis. Both gene expressions differed among primary tumors and metastatic tumors, especially in metastatic sites. DTP might be useful to evaluate the 2 gene expressions in colorectal cancer. Further studies would be needed to clarify the mechanisms of difference of gene expressions in cancerous and stromal tissues, or in primary tumors and metastatic tumors.
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PMID:[Thymidylate synthase and dihydropyrimidine dehydrogenase gene expressions in colorectal cancer using the Danenberg tumor profile method]. 1522 6

The goal of chemotherapy is the elimination of tumor cells from the host. This is achieved by the use of therapeutic agents that are often more harmful to normal tissues than to the targeted tumor. Many chemotherapeutic agents are designed to damage cell replication machinery either directly at the level of DNA or indirectly, by inhibiting enzymes involved with DNA repair and synthesis. Novel therapeutic agents that exert their effects at signal transduction pathways have advanced chemotherapy; however, a role for the classic chemotherapeutic agents remains. These classic agents are associated with tumor cell resistance, toxicity, and occasionally secondary neoplasia. Current practices for the dosing of therapeutic agents rely on height and body surface measurements or drug monitoring and Bayesian adaptive control. Pharmacogenetics is emerging as an alternate approach to managing chemotherapy that may prevent undertreatment while avoiding overtreatment and associated toxicities. By determining the polymorphic genetic makeup of the host and, in some instances, the altered genetic expression of the tumor, chemotherapy can be tailored for interindividual response and toxicity avoidance. Chemotherapy is particularly applicable to the pharmacogenetic approach to tailored therapy for a number of reasons. The margin of safety is low with chemotherapeutic agents. Some drugs require biotransformation for activation. Drug activation correlates with toxicity. The pathways of drug clearance or inactivation exhibit polymorphic differences. Interindividual, race-specific, and age-related responses to chemotherapeutic agents are common. Last, drug resistance can be inherent to the tumor as a result of the suppression of apoptosis. Variations in response and toxicity to a specific drug can be caused by alterations in drug-metabolizing enzymes or receptor expression. These effects can be classed as pharmacokinetic and pharmacogenetic differences. Some of the genes known to display polymorphic differences include FLT3 receptor tyrosine kinase, FCG3RA IgG FC receptor, thymidylate synthase, methylenetetrahydrofolate reductase, thiopurine S-methyltransferase, dihydropyrimidine dehydrogenase, aldehyde dehydrogenase, glutathione S-transferase, uridine diphosphate glyuronosyl transferases, N-acetyl transferases, cytochrome P450, and the DNA repair enzymes XPD and XRCC1. To be successful a pharmacogenetic approach to individualized chemotherapy must selectively take advantage of a determination of direct enzyme activity, gene expression, and genotype.
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PMID:Pharmacogenetics in cancer chemotherapy: balancing toxicity and response. 1522 71

Thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) are considered to be key enzymes affecting the prognosis for patients with various cancers. We tried to prove the correlation of TP and DPD expression in hepatocellular carcinoma (HCC) and liver metastasis. We quantified TP and DPD levels by an enzyme-linked immunosorbent assay (ELISA) in the tumor (T) and adjacent normal tissue (N) obtained from 8 HCC patients, and 11 liver metastasis patients together with 9 of their primary cancers. TP levels were higher in the primary cancer, liver metastasis, and HCC compared with each adjacent tissue. TP levels were higher in HCC than in liver metastasis, and TP levels in the adjacent tissues of HCC were also higher than those in adjacent tissues of liver metastasis. TP levels were higher in liver metastasis than in primary cancer, and TP levels in adjacent tissues of liver metastasis were also higher than those in adjacent tissues of primary cancer. However, there were no differences in TP T/N ratio between HCC and liver metastasis, and between primary cancer and liver metastasis. DPD levels were lower in the liver metastasis compared with the adjacent liver tissues, and DPD levels in liver metastasis or its adjacent liver tissues were higher than those in primary cancer or its adjacent tissues. There were no differences in DPD T/N ratio between HCC and liver metastasis, and between primary cancer and liver metastasis. Thus, we demonstrated that TP was highly expressed in liver malignancy. We may be able to increase the success of anticancer chemotherapy for liver malignancy while decreasing the side effects by analysis of T/N ratios in TP, DPD, and TP/DPD in addition to TP expression.
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PMID:Thymidine phosphorylase and dihydropyrimidine dehydrogenase expression in hepatocellular carcinoma and metastatic liver cancer. 1525

(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU, Brivudin, Zostex, Zerpex, Zonavir), now more than 20 years after its discovery, still stands out as a highly potent and selective inhibitor of herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) infections. It has been used in the topical treatment of herpetic keratitis and recurrent herpes labialis and the systemic (oral) treatment of herpes zoster (zona, shingles). The high selectivity of BVDU towards HSV-1 and VZV depends primarily on a specific phosphorylation of BVDU to its 5'-diphosphate (DP) by the virus-encoded thymidine kinase (TK). After further phosphorylation (by cellular enzymes), to the 5'-triphosphate (TP), the compound interferes as a competitive inhibitor/alternate substrate with the viral DNA polymerase. The specific phosphorylation by the HSV- and VZV-induced TK also explains the marked cytostatic activity of BVDU against tumor cells that have been transduced by the viral TK genes. This finding offers considerable potential in a combined gene therapy/chemotherapy approach for cancer. To the extent that BVDU or its analogues (i.e., BVaraU) are degraded (by thymidine phosphorylase) to (E)-5-(2-bromovinyl)uracil (BVU), they may potentiate the anticancer potency, as well as toxicity, of 5-fluorouracil. This ensues from the direct inactivating effect of BVU on dihydropyrimidine dehydrogenase, the enzyme that initiates the degradative pathway of 5-fluorouracil. The prime determinant in the unique behavior of BVDU is its (E)-5-(2-bromovinyl) substituent. Numerous BVDU analogues have been described that, when equipped with this particular pharmacophore, demonstrate an activity spectrum characteristic of BVDU, including selective anti-VZV activity.
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PMID:(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU). 1538 33

To evaluate the antitumor and antimetastatic efficacy of oral fluoropyrimidines, alone and combined with taxane on human breast cancer xenografts model, we developed a breast cancer model that spontaneously metastasizes to the lung by orthotopic implantation of MDA-MB-435S-HM tumors into the mammary fat pad (mfp) of SCID mice. The activity of the 5-fluorouracil (5-FU)-degrading enzyme dihydropyrimidine dehydrogenase (DPD) was significantly higher in the metastatic tumors than in the primary tumors. Based on this enzymatic characteristic of pulmonary metastases of breast cancer in regard to 5-FU metabolism, we investigated the antitumor activity of two types of oral 5-FU prodrugs, with and without paclitaxel, on both orthotopically implanted breast tumors and metastatic lung tumors in mice. The drugs and doses used were: S-1, a new oral DPD-inhibiting fluoropyrimidine (DIF) 8.3 mg/kg/day, capecitabine 360 mg/kg/day as a non-DIF, and paclitaxel 50 mg/kg, all of which display minimal toxicity in mice. In the primary tumors, paclitaxel and S-1 displayed a significant antitumor activity, with 57 and 41%, respectively inhibition of tumor growth (p < 0.01), but capecitabine had no effect. When S-1 and paclitaxel were combined, they synergistically caused tumor regression (tumor growth inhibition ratio 94%, p < 0.01) in mice compared to capecitabine plus paclitaxel, without any toxicity. In the pulmonary metastasis model, paclitaxel, and both S-1 alone and combined with paclitaxel, but not capecitabine alone or combined with paclitaxel, diaplayed almost complete antimetastatic activity. These results strongly suggest that combination of S-1, as a DIF with taxanes will show a potent high antitumor and antimetastatic effect on refractory human breast cancers, especially those expressing strong DPD activity.
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PMID:Antimetastatic and anticancer activity of S-1, a new oral dihydropyrimidine-dehydrogenase-inhibiting fluoropyrimidine, alone and in combination with paclitaxel in an orthotopically implanted human breast cancer model. 1554 87

The treatment of colorectal cancer has advanced over the past several years with the introduction of several active agents. Determining which patients to treat with chemotherapy and choosing optimal treatment would allow practioners to maximize the benefit of chemotherapy. Several prognostic and predictive markers have been identified and include oncogenes, tumor suppressor genes, genes involved in angiogenic and apoptotic pathways and cell proliferation, and those encoding targets of chemotherapy. Specifically, prognostic markers include deletion of 18q (DCC), p27 and microsatellite instability. Predictive markers are those that may determine efficacy of drugs used in colorectal cancer such as fluropyrimidines and oxaliplatin. Alterations in gene expression, protein expression and polymorphic variants in genes encoding thymidylate synthase, dihydropyrimidine dehydrogenase, and thymidine phosphorylase and excision repair cross-complementing genes (ERCC1) may be useful as markers for clinical drug response, survival and host toxicity. The integration of these prognostic and predictive markers would allow individualized treatment for patients, maximizing therapeutic effect and minimizing exposure to toxicity.
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PMID:Tailored chemotherapy for colorectal cancer: a new approach to therapy. 1558 Oct 57


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